Heart disease remains one of the leading causes of death. The high incidence of heart disease has led to the identification of various risk factors that may be controlled in an effort to reduce such disease. One risk factor is hypercholesterolemia, which is a condition of high blood levels of cholesterol. Cholesterol is a fatty substance that is made by the liver, and also is present in many foods. Cholesterol circulates in the blood associated with several forms of lipoproteins. Some of these forms are now referred to as "good" forms of cholesterol, while others are "bad". For example, one such lipoprotein with which cholesterol associates is referred to as low-density lipoprotein or LDL. LDL-cholesterol (LCL-C) is the form in which cholesterol leaves the liver destined for cells throughout the body. High levels of LDL-C are bad, because they have been shown to cause rapid clogging of coronary arteries with fatty deposits, resulting in the disease known as atherosclerosis, which often leads to heart attacks. A great deal of effort is currently underway to get people to reduce their levels of LDL-C, for example, by modifying diet and exercise.
In contrast, a good form of cholesterol is that associated with high-density lipoprotein, ie, HDL-cholesterol (HDL-C). This is the form in which cholesterol is pulled out of cells and goes back to the liver for disposal.
A modified form of LDL is known as lipoprotein(a), "Lp(a)". It consists of LDL covalently linked through a disulfide bond to apolipoprotein(a), "apo(a)". Lp(a) cholesterol appears to be a bad form of cholesterol, since elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, and restenosis following balloon angioplasty. In fact, Lp(a) appears to be an excellent predictor for stroke. Accordingly, high concentrations of Lp(a) is one of the major risk factors leading to death from heart disease.
We have now discovered that retinoids are effective in lowering plasma concentrations of Lp(a). This invention thus provides a method for lowering plasma levels of Lp(a) comprising administering a retinoid.
Retinoids are a class of natural and synthetic organic molecules which modulate the activity of retinoid responsive genes, mRNAs, and proteins. Some activities of retinoids occur by interaction with families of nuclear receptors, including the retinoic acid receptors and the retinoid X receptors. Vitamin A is a natural retinoid known as retinol. "Vitamin A acid" is retinoic acid. Retinoids have been reported to have a number of biological activities. For example, they are said to be potent agents for control of both cellular differentiation and proliferation. They have been reported to moderate the growth of tumors and to affect the immune system, see Gale, Progress in Medicinal Chem. 1993;30, Ellis and Luscombe ed., Elsevier Publishers.
Retinoids have also been reported to have effects on plasma concentrations of lipoproteins. For example, Lyons, et al., Br. J. Dermatology 1982;107:591-5, reported a decrease in HDL-C levels in patients given 13-cis-retinoic acid. Ringer, et al., Am. J. Chem. Nutr. 1991;53:688-94, reported an increase in HDL concentrations in patients given .beta.-carotene, but did not find any changes in apolipoprotein A or B levels. Katocs, et al., U.S. Pat. No. 5,219,888, reported that retinoids increase plasma HDL levels.
There have been no reports that retinoids effect plasma levels of Lp(a). We have now discovered that plasma Lp(a) can be lowered by administering retinoids, and accordingly an object of this invention is to provide a method for lowering Lp(a), and thereby treating and preventing coronary artery disease.